Regulatory T cells (Tregs) suppress autoimmunity and inflammation and are exploited by a variety of solid tumors to muffle anti-tumor immunity. The identity of Tregs is defined by Foxp3 and their function depends on the transcription factor. However, it has not been clear just how dependent the gene-expression programs that define Treg cell function are on its continuing activity in differentiated Treg cells. Researchers co-led by Ludwig MSK Director Alexander Rudensky used a mouse model of inducible Foxp3 protein degradation to explore the matter. They reported in an October Nature Immunology paper that while Foxp3 is required to establish the identity and function of “young” Treg cells, its loss under steady state has no effect on the immunosuppressive function of mature Tregs and is accompanied by only minimal changes to their gene expression patterns. Foxp3 activity is, however, required for appropriate function and fitness under conditions of intense inflammation, even in mature Treg cells. The researchers also found that Foxp3 loss caused the preferential destabilization and dysfunction of intratumoral Tregs in mouse models, enabling anti-tumor immune responses and the shrinkage of tumors without inducing adverse side-effects. The researchers suggest this presents a unique opportunity to develop immunotherapies for tumors that harbor large numbers of these immunosuppressive cells.
Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells
Nature Immunology, 2025 October 8